In a study related to the pain-producing mechanism, a receptor of capsaicin (8-methyl-N-vanillyl-6-nonenamide), which is a main pungent taste component of chili pepper, (TRPV1 receptor) was cloned in 1997 (Caterina M J, Schumacher M A, Tominaga M, Rosen T A, Levine J D, and Julius D., Nature, Vol. 389, pp. 816-824, 1997). The TRPV1 receptor, which is a receptor that recognizes capsaicin, frequently expressed in primary sensory neurons involved in the sense of pain, and sensory afferent fibers containing C-fiber nerve endings. Thereafter, many TRP family receptors were cloned.
The structures of the TRP family receptors are similar to each other. The TRP family receptors each have a six transmembrane domain, and the N-terminal and the C-terminal of the molecule are disposed in a cell. In response to capsaicin stimulation, an acid (pH 6.0 or less), or heat (43° C. or higher), the TRPV1 receptor allows cations such as a calcium ion and a sodium ion to flow into a cell. Accordingly, considering the expression sites of the TRPV1 receptor and the action of capsaicine, a marked contribution of the TRPV1 receptor to the excitement of nerve was assumed. Furthermore, contributions of the TRPV1 receptor to living organisms have been elucidated from information disclosed in many previous reports. In particular, in a mouse in which the TRPV1 receptor has been deleted (TRPV1 knockout mouse), enhancement of heat sensitivity due to neuropathic pain is not observed, development of edema is suppressed in a Complete Freund's Adjuvant (CFA)-induced inflammatory pain model (Szabo A, Helyes Z, Sandor K, Bite A, Pinter E, Nemeth J, Banvolgyi A, Bolcskei K, Elekes K, and Szolcsanyi J, Journal of Pharmacology And Experimental Therapeutics, Vol. 314, pp. 111-119, 2005), and desensitization action by a TRPV1 receptor agonist disclosed in a previous report exhibits an analgetic effect in a neuropathic pain model and an inflammatory pain model, and thus, an involvement of the TRPV1 receptor in pain has been suggested (Rashid M H, Inoue M, Kondo S, Kawashima T, Bakoshi S, and Ueda H, Journal of Pharmacology And Experimental Therapeutics, Vol. 304, pp. 940-948, 2003).
Application of capsaicin causes a temporary acute pain, but then induces desensitization to cause an analgetic effect. On the basis of this characteristic, many TRPV1 receptor agonists, such as a capsaicin cream, have been under development as analgetic drugs (Saper J R, Klapper J, Mathew N T, Rapoport A, Phillips S B, and Bernstein J E, Archives of Neurology, Vol. 59, pp. 990-994, 2002).
Recently, it has been reported that, in dorsal root ganglion cells of a diabetic pain model rat induced by administering streptozotocin, depolarization due to capsaicin stimulation is accelerated, that is, the sensitivity of the TRPV1 receptor is enhanced. Thus, an involvement of the TRPV1 receptor in diabetic pain has been suggested (Hong S and Wiley J W, The Journal of Biological Chemistry, Vol. 280, pp. 618-627, 2005). In addition, it has been reported that the desensitization action of capsaicin, which is a TRPV1 receptor agonist, is effective for improving the bladder function, and thus, a contribution to urination has also been suggested (Masayuki Takeda and Isao Araki, Nippon Yakurigaku zasshi (Folia Pharmacologica Japonica), Vol. 121, pp. 325-330, 2003). Furthermore, contraction of bronchia caused by capsaicin stimulation, an inhibition effect of a TRPV1 receptor antagonist for this action, and the like have also been reported, and thus, an involvement in respiratory organs has also been suggested. It has been elucidated that the TRPV1 receptor is involved in various diseases. From the information described above, TRPV1 receptor regulators that modulate the function of the TRPV1 receptor have been expected to be useful.
Among such TRPV1 regulators, agonists that stimulate the TRPV1 receptor to induce desensitization and antagonists are expected to be useful in treating various diseases. Among these agonists and antagonists, since the agonists cause pain involving temporary acute stimulation and so forth, TRPV1 receptor antagonists that do not induce such excitation due to stimulation have attracted attention. Currently, compounds having a TRPV1 receptor antagonism are expected to be widely useful for, for example, analgetic drugs, therapeutic drugs for urinary incontinence, and therapeutic drugs for respiratory diseases.
Pain is defined as “an unpleasant, sensory and emotional experience that is caused by a substantial or latent lesion of a tissue, and a sensory and emotional experience that is described using such an expression”. Pain can be roughly divided into three categories: 1. nociceptive pain, 2. neuropathic pain, and 3. psychogenic pain.
The nociceptive pain is physiological pain caused by mechanical stimuli, thermal stimuli, or chemical stimuli. In general, the nociceptive pain acute pain and serves as a biosensor based on unpleasant sensory experiences to protect the body from danger. It has been thought that pain such as rheumatism is surely acute pain. However, a prolonged period from the onset thereof and the chronicity of inflammation bring about chronic pain.
Hyperalgesia to thermal to thermal stimuli or mechanical stimuli arises after tissue damage or during inflammation. The sensitization of receptors to a pain-inducing material and pain-inducing stimuli is reported in explanation of the hyperalgesia to thermal stimuli or mechanical stimuli. Examples thereof include sensitization of pain receptors due to inflammatory mediators occurring in local inflammation and a decrease in the pH therein, an increase in reactivity to bradykinin and histamine due to an increase in the temperature of local inflammation, and sensitization due to nerve growth factor (NGF) (reference: Kazuo Hanaoka, Itami-Kiso, Shindan, Chiryo- (Pain-Base, Diagnosis, and Therapy-), Asakura Shoten, 2004). Specific examples thereof include chronic rheumatism and knee osteoarthritis, which are typical examples. Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for treatment of inflammatory pain due to pain chronic rheumatism and knee osteoarthritis for a long period of time. However, the use thereof is restricted because of side effects due to a disorder of apparatus digestorius and renal disorder. Furthermore, although cyclooxygenase-2-selective inhibitors (COX2 inhibitors) have been developed for reducing the side effects of NSAIDs, there is concern abut side effect that can lead to cardiac insufficiency which has become a social problem. Accordingly, an inflammatory pain therapeutic agent having higher efficacy in oral administration and having fewer side effects is required.
Postoperative pain is basically inflammatory pain which tissue damage accompanies, and includes factors of neurogenic pain factor derived from nerve injury. Postoperative pain is broadly divided into somatic pain and visceral pain. Somatic pain is further divided into superficial pain and deep pain. Among these, when severe postoperative pain is left untreated, nerve sensitization occurs; hence, pain is also evoked by innocuous stimuli, such as a touch and a press (allodynia). When such pain occurs, there are many intractable cases that cannot be controlled by nerve block therapy and the administration of drugs, such as NSAIDs, antiepileptic drugs, and opioid agonists. Furthermore, these drugs used have side effects. For example, the NSAIDs have side effects due to disorder of apparatus digestorius organs and renal disorder. In the antiepileptic drugs, carbamazepine and Phenyloin have side effects, such as tibutation, eruption, digestive symptoms, and cardiotoxicity; and Gabapentin has side effects such as somnolence and vertigo. The opioid agonists have side effects such as constipation. Accordingly, a postoperative pain therapeutic agent having higher efficacy and having fewer side effects is required.
Neuropathic pain is pain caused by primary damage of a certain portion in a neurotransmission system ranging from a periphery to center or caused by a malfunction thereof (Kenjiro Dan, Zusetsu Saishin Masuikagaku sirizu 4, Itami no rinsho (Textbook of anesthesiology 4, Fully illustrated) Chapter 1, 1998, Medical View Co., Ltd.).
Nerve injuries that cause neuropathic pain are typically external injuries or lesions on a peripheral nerve, a nerve plexus, or perineural soft-tissue. However, neuropathic pain is also caused by lesions on central somatosensory pathways (for example, ascending somatosensory pathways in spinal cord, brainstem, the thalamic or cortex level, and the like). For example, neuropathic pain is possibly caused by any of neurodegenerating diseases, osteolytic disease, metabolic disorder, cancer, infection, inflammation, after surgical operation, external injuries, radiotherapy, treatment using anticancer agents, and the like. However, the pathophysiological mechanism, or in particular, the molecular mechanism of the onset, has not yet been completely elucidated.
Allodynia is known as an example of an abnormal skin reaction characterizing neuropathic pain is allodynia. Allodynia is a state in which a person feels pain even with stimulation that would not result in normal person feeling pain. In allodynia, pain is evoked by tactile stimulus. That is, fundamental characteristics of allodynia are qualitative change in sensory responses and a low pain threshold. In postherpetic neuralgia, which is representative of neuropathic pain, it is confirmed that 87% of patients have allodynia. It is alleged that the strength of pain in postherpetic neuralgia is proportional to the degree of allodynia. Allodynia, which is a symptom that markedly constrains patients' freedom, draws attention as a therapeutic target of postherpetic neuralgia.
Herpes is a disease in which an infected herpes virus is neurons to cause onset, and 70% of herpes patients feel severe pain. This pain disappears as the disease is treated. However, about 10% of the patients suffers from so-called postherpetic neuralgia in which the pain remains for many years even after the disease is cured. On pathogenetic mechanism, it is said that the herpes virus proliferates again from a nerve ganglion, and nerve lesions generated during this proliferation accelerate reorganization of synapses, thus causing allodynia, which is neuropathic pain. In clinical settings, elderly people are more likely to develop the postherpetic neuralgia, and 70% or more of the cases of postherpetic neuralgia occur in patients 60 years old or older. Examples of a therapeutic agent used include anticonvulsant agents, non-steroidal anti-inflammatory agents, steroids, and the like, but there is no complete therapy (reference: Kazuo Hanaoka, Itami-Kiso, Shindan, Chiryo- (Pain-Base, Diagnosis, and Therapy-), Asakura Shoten, 2004).
Diabetic pain is broadly categorized into acute pain that occurs when hyperglycemia is rapidly remedied and chronic pain that occurs due to factors such as demyelination or nerve regeneration. Among these types of diabetic pain, the chronic pain is neuropathic pain due to inflammation of the dorsal root ganglion caused by a decrease in the bloodstream due to diabetes, and spontaneous firing of neurons and excitability caused by the subsequent regeneration of nerve fibers. Non-steroidal anti-inflammatory agents, antidepressant agents, capsaicin creams and the like are used for therapy. However, there is no perfect therapeutic agent for treatment of diabetic pain that can cure all the types of diabetic pain using a single agent (Reference: Iyaku no ayumi (Progress in Medicine)(Journal of Clinical and Experimental Medicine), Vol. 211, No. 5, 2004, Special feature “Itami shigunaru no seigyo kiko to saishin chiryo ebidensu” (“Control mechanisms of Pain Signal and Latest Evidence-based Therapy”)).
In neuropathic pain, analgesic treatment for patients who complain of a chronic pain symptom that interferes with their daily life directly improves the quality of life. However, it is believed that central analgetic agents represented by morphine, non-steroidal anti-inflammatory analgesic agents, and steroids are not effective against neuropathic pain. In practical pharmacotherapy, antidepressant agents such as amitriptyline; antiepileptic drugs such as Gabapentin, Pregabalin, carbamazepine, and phenyloin; and antiarrhythmic agents such as mexiletine are also used and prescribed for the treatment of neuropathic pain. However, it is known that these drugs have the following side effects: Amitriptyline causes side effects such as dry mouth, drowsiness, sedation, constipation, and dysuria. Carbamazepine and phenyloin cause side effects such as light-headedness, eruption, digestive apparatus symptoms, and cardiotoxicity. Gabapentin causes side effects such as somnolence and vertigo. Mexiletine causes side effects such as vertigo and digestive apparatus symptoms. These drugs, which are not specific neuropathic pain therapeutic agents, have poor dissociation between drug efficacy and side effect, thus, resulting in low treatment of satisfaction. Accordingly, a neuropathic pain therapeutic agent that exhibits a higher efficacy in oral administration and that have fewer side effects is required.
Recently, compounds having a TRPV1 receptor antagonism have been studied. Known heterocyclic compounds each having an amide bond are disclosed in, for example, PCT Publication No. 03/049702 pamphlet (Patent Document 1), PCT Publication No. 04/056774 pamphlet (Patent Document 2), PCT Publication No. 04/069792 pamphlet (Patent Document 3), PCT Publication No. 04/100865 pamphlet (Patent Document 4), PCT Publication No. 04/110986 pamphlet (Patent Document 5), PCT Publication No. 05/016922 pamphlet (Patent Document 6), PCT Publication No. 05/030766 pamphlet (Patent Document 7), PCT Publication No. 05/040121 pamphlet (Patent Document 8), PCT Publication No. 05/046683 pamphlet (Patent Document 9), PCT Publication No. 05/070885 pamphlet (Patent Document 10), PCT Publication No. 05/095329 pamphlet (Patent Document 11), PCT Publication No. 06/006741 pamphlet (Patent Document 12), PCT Publication No. 06/038871 pamphlet (Patent Document 13), and PCT Publication No. 06/058338 pamphlet (Patent Document 14). However, these patent documents do not disclose heterocyclidene acetamide derivatives.
Examples of the related art that disclose a compound having a heterocyclidene skeleton include that are PCT Publication No. 94/26692 pamphlet (Patent Document 15), PCT Publication No. 95/06035 pamphlet (Patent Document 16), PCT Publication No. 98/39325 pamphlet (Patent Document 17), PCT Publication No. 03/042181 pamphlet (Patent Document 18), Japanese Patent Application Laid-open No. 2001-213870 (Patent Document 19), PCT Publication No. 06/064075 pamphlet (Patent Document 20), Journal of Heterocyclic Chemistry, Vol. 22, No. 6, pp. 1511-18, 1985 (Non-Patent Document 1), Tetrahedron Letters, Vol. 42, No. 18, pp. 3227-3230, 2001 (Non-Patent Document 2), and Chemical Pharmaceutical Bulletin, Vol. 47, No. 3, pp. 329-339, 1999 (Non-Patent Document 3).
Patent Document 15 discloses, as a muscle relaxant, a compound with a structure which has a 2H-1-benzopyran-4-ylidene skeleton or a 1,2,3,4-tetrahydro-4-quinolidene skeleton and in which a hydrogen atom, an alkyl group, or a cycloalkyl group is bonded to the N atom of the acetamide structure. However, a compound in which a substituted aryl group, heteroaryl group, or the like is bonded to the N atom is not disclosed. Patent Documents 16 to 18 disclose, as an arginine vasopressin antagonist or an oxytocin antagonist, a compound with a specific structure which has a 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzodiazepine skeleton and in which an aryl carbonyl group substituted an aryl is bonded to the N atom of the 1-position of the skeleton.
Patent Document 19 discloses, as a 2-(1,2-benzisothiazol-3(2H)-ylidene 1,1-dioxide) acetamide derivative used as a novel charge-control agent for a toner for electrostatography, a specific compound in which the N atom of the acetamide has a substituted phenyl group.
Patent Document 20 discloses, as an amide derivative of a 2,3-dihydro-1-oxo-1H-isoquinolin-4-ylidene used as a calpain inhibitor, a compound with a specific structure which has a sec-butyl group at the 3-position.
In a report related to the synthesis of an oxyindole derivative, Non-Patent Document 1 discloses 2-(1,2-dihydro-2-oxo-3H-indol-3-ylidene)-N,N-dimethyl-acetamide. However, a substituted aryl group or heteroaryl group, or the like is not bonded to the N atom.
Non-Patent Document 2 discloses, as a (1,2,3,4-tetrahydro-2-oxo-5H-1,4,-benzodiazepin-5-ylidene)acetamide derivative used for an N-methyl-D-aspartate (NMDA) antagonist, a compound with a specific structure in which a phenyl group is bonded to the N atom of the acetamide.
Non-Patent Document 3 discloses, as a (2,3,4,5-tetrahydro-1H-1-benzodiazepin-5-ylidene)acetamide derivative used as a nonpeptide arginine vasopressin antagonist, a compound with a specific structure in which a 2-pyridylmethyl group is bonded to the N atom of the acetamide, and the benzodiazepine skeleton does not have a substituent.
Patent Documents 15 to 20 and Non-Patent Documents 1 to 3 disclose compounds each having a heterocyclidene skeleton, but the antagonism of the TRPV1 receptor is not disclosed or suggested.
In the development of pharmaceuticals, it is required to satisfy strict criteria for not only target pharmacological activity but also absorption, distribution, metabolism, excretion, and the like. With respect to drug interactions, desensitization or tolerance, digestive absorption in oral administration, the rate of transfer to a small intestine, the rate of absorption and first-pass effect, an organ barrier, protein binding, induction of a drug-metabolizing enzyme, an excretion pathway and body clearance, a method of administration (an application site, a method, and purpose), and the like, various agenda are required. However, a drug that satisfies these requirements is seldom discovered.
These comprehensive problems in drug development also exist for TRPV1 receptor antagonists, and TRPV1 receptor antagonists have not yet been released onto the market. More specifically, compounds having a TRPV1 receptor antagonism also include problems in terms of usefulness and safety. For example, these compounds have low metabolic stability and oral administration of these compounds is difficult; these compounds exhibit inhibitory activity of the human ether-a-go-go related gene (hERG) channel, which may cause arrhythmia, and pharmacokinetics of these compounds are not satisfactory. Accordingly, a compound in which these problems are solved and which has high activity has been desired.
In addition, a compound that causes fewer of the above-mentioned side effects than known drugs that are currently used in the treatment of pain including the above-described types of neuropathic pain has been desired.